This is a competitive renewal application of the Wayne State Principal Investigator's (Rosenberg) grant award, R01MH59299. Obsessive compulsive disorder (OCD) is a severe, prevalent, and chronically disabling disorder that emerges during childhood in as many as 50% of all cases. The overall goal of this project, which combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites - Wayne State (neuroimaging of pediatric OCD), University of Michigan (family and molecular genetic studies of early-onset OCD) and University of Toronto (extensive genetic studies of glutamate receptor and transporter genes in OCD) - is to exploit the emerging field of imaging genetics in a critical test of the glutamate hypothesis of OCD. Preliminary studies from Rosenberg's group (R01MH59299, K24MH02037) suggest that a glutamatergically-mediated thalamocortical-striatal dysfunction may serve as a pathophysiological marker in pediatric OCD. Independent findings by the Hanna (R01MH53876, K20MH01065) and the Arnold and Kennedy groups demonstrate a significant association of the glutamate transporter gene, SLC1A1, and glutamate receptor gene, GRIN2B, with early-onset OCD. Building on long-standing existing collaborations among the three sites, exciting new pilot data in pediatric OCD patients demonstrates a significant association between regional brain glutamatergic concentrations, particularly in the anterior cingulate and the GRIN2B-rs1019385 polymorphism. Significant associations between increased left, but not right orbital frontal and increased anterior cingulate volume (R>L) with the rs1805476 variant of GRIN2B were identified in OCD patients. The GRIN2B-rs1019385 variant exhibited a non-significant trend towards association with decreased left but not right caudate volume. The SLC1A1 rs3056-AA genotype was significantly associated with increased right and left thalamic volume. Thus, GRIN2B and SLC1A1 sequence variations may be associated with differences in volume and glutamatergic concentrations within brain regions implicated in the pathogenesis of OCD. High field (3 Tesla) proton magnetic resonance spectroscopy (1H MRS) can uniquely distinguish the subcomponents of the glutamatergic resonance (glutamate and glutamine), as well as measure other compounds including the putative neuronal marker, N-acetyl-aspartate, choline compounds and creatine. Targeted 1H MRS and volumetric imaging at 3T at the Children's Hospital of Michigan at Wayne State will be combined with genotyping of 37 polymorphisms in the genes encoding GRIN2B and SLC1A1 (University of Toronto) to examine the effects of these variants on thalamocortical-striatal circuitry in 200 pediatric OCD patients, 7-19 years, and 200 age and sex-matched healthy controls. The combined study of biological, genetic and behavioral/symptom variables enacts the call for translational approaches to mental illness outlined in PA-07- 092, Collaborative R01s for Clinical and Services Studies of Mental Disorders, which may lead to a better understanding of pediatric OCD and, in turn, to new diagnostic and treatment approaches.